Drug Delivery through the Blood-brain Barrier without Invasion

Abraham Ratih^*
*Correspondence: Abraham Ratih, Department of Pharmaceutics, China Pharmaceutical University, Nanjing 211198, China, Email:

Introduction

The human brain, a complex and vital organ, is protected by a selective barrier known as the blood-brain barrier (BBB). This barrier is crucial for maintaining the brain's homeostasis by regulating the entry of substances from the bloodstream into the Central Nervous System (CNS). While this protective mechanism is essential for safeguarding the brain against toxins and pathogens, it also poses significant challenges for drug delivery, particularly in treating neurological disorders. Traditional methods of drug delivery often involve invasive techniques, which can lead to complications and increased patient discomfort. Therefore, the development of non-invasive strategies for delivering therapeutic agents across the BBB has become a focal point in pharmaceutical research [1].

The blood-brain barrier is formed by specialized endothelial cells that line the brain's capillaries. Unlike other blood vessels, these cells are tightly connected by tight junctions, which restrict the passive diffusion of substances. The BBB is further supported by astrocytes, pericytes and the extracellular matrix, which contribute to its integrity and functionality. This intricate structure allows for selective permeability, enabling essential nutrients like glucose and amino acids to enter while blocking harmful substances, including many drugs [2].

Description

The primary function of the BBB is to maintain the brain's microenvironment, ensuring that it remains stable and conducive for neural activity. The barrier selectively allows the passage of essential substances while restricting the entry of potentially harmful compounds. It plays a pivotal role in protecting the brain from inflammatory responses, pathogens and fluctuations in systemic circulation. The restrictive nature of the BBB presents a significant challenge for delivering pharmacological agents intended for CNS disorders. Many drugs that are effective in other parts of the body fail to reach therapeutic concentrations in the brain. Traditional delivery methods, such as systemic administration, often result in limited bioavailability and potential side effects due to systemic circulation. The physicochemical properties of drugs influence their ability to cross the BBB. Factors such as molecular size, charge, lipophilicity and solubility play a crucial role. Generally, small, lipophilic molecules are more likely to penetrate the BBB than larger, hydrophilic compounds [3].

Neurological diseases such as Alzheimer's, Parkinson's and multiple sclerosis require targeted drug delivery to the brain. The inability to effectively deliver therapeutics exacerbates disease progression and limits treatment options, highlighting the urgent need for innovative delivery systems. Nanotechnology offers a promising approach for enhancing drug delivery across the BBB. Nanoparticles, ranging from liposomes to dendrimers, can be engineered to improve drug solubility, stability and targeting capabilities. Size and Surface Modifications: Nanoparticles can be designed at a nanoscale, enabling them to exploit endogenous transport mechanisms. Surface modifications, such as coating with Polyethylene Glycol (PEG) or specific ligands, can enhance the particles' ability to cross the BBB. Nanoparticles have been utilized to deliver a variety of therapeutic agents, including chemotherapeutics, antibodies and gene therapy vectors. Studies have shown that nanoparticles can significantly enhance the brain delivery of these agents while minimizing systemic exposure. Certain peptides or small molecules can transiently disrupt tight junctions, allowing larger molecules to cross the barrier. For example, bradykinin and its analogs can increase BBB permeability temporarily. Utilizing inhibitors of efflux transporters like P-glycoprotein can enhance the accumulation of drugs in the brain. Neuroinflammatory conditions can lead to increased BBB permeability. Exploiting this characteristic, researchers are investigating the delivery of therapeutic agents during such conditions to enhance drug uptake [4].

FUS employs high-frequency sound waves focused on specific brain regions. When combined with microbubbles, the ultrasound can induce mechanical oscillations that temporarily open the tight junctions, allowing drugs to enter the brain. FUS can be precisely targeted to specific brain areas, minimizing off-target effects. Unlike traditional methods, FUS does not require surgical intervention, reducing the risk of complications and patient discomfort. FUS is being investigated for delivering chemotherapeutics in brain tumors and for treating neurodegenerative diseases. Early clinical trials have shown promising results in enhancing drug delivery while maintaining safety. Some therapeutic agents can be designed to exploit receptor-mediated transcytosis, a natural transport mechanism that allows substances to cross the BBB. For instance, ligands targeting transferrin receptors can facilitate the transport of drugs or nanoparticles across the barrier. Intranasal administration bypasses the BBB by directly delivering drugs to the CNS via the olfactory and trigeminal nerve pathways. This route has gained attention for delivering peptides, proteins and even small molecules directly to the brain [5].

Conclusion

The challenge of delivering drugs across the blood-brain barrier remains a critical hurdle in treating neurological disorders. Traditional invasive methods often fall short in terms of efficacy and safety, underscoring the need for innovative, non-invasive approaches. Advances in nanotechnology, biochemical modulation, focused ultrasound and alternative delivery methods offer promising avenues for overcoming the BBB's restrictive nature. As research continues to evolve, the potential for these strategies to transform the landscape of CNS drug delivery is significant. Future developments may lead to more effective treatments for debilitating neurological conditions, ultimately improving patient outcomes and quality of life. Continued interdisciplinary collaboration among neuroscientists, pharmacologists and biomedical engineers will be crucial in bringing these innovative drug delivery systems to clinical practice. The journey toward effective non-invasive drug delivery through the BBB is ongoing, but the strides made thus far signal a hopeful future for those affected by neurological diseases.

Acknowledgement

None.

Conflict of Interest

There are no conflicts of interest by author.

References

1. Spencer, Brian J. and Inder M. Verma. "Targeted delivery of proteins across the blood–brain barrier." Proc Natl Acad Sci 104 (2007): 7594-7599.

   Google Scholar, Crossref, Indexed at

2. Zhang, Bo, Xiyang Sun, Heng Mei and Yu Wang, et al. "LDLR-mediated peptide-22-conjugated nanoparticles for dual-targeting therapy of brain glioma." Biomater 34 (2013): 9171-9182.

   Google Scholar, Indexed at

3. Ma, Feihe, Liu Yang, Zhuorui Sun and Jinjin Chen, et al. "Neurotransmitter-derived lipidoids (NT-lipidoids) for enhanced brain delivery through intravenous injection." Sci Adv 6 (2020): eabb4429.

   Google Scholar, Crossref, Indexed at

4. Fenno, Lief, Ofer Yizhar and Karl Deisseroth. "The development and application of optogenetics." Annu Rev Neurosci 34 (2011): 389-412.

   Google Scholar, Crossref, Indexed at

5. Aho, Velma TE, Madelyn C. Houser, Pedro AB Pereira and Jianjun Chang, et al. "Relationships of gut microbiota, short-chain fatty acids, inflammation and the gut barrier in Parkinson’s disease." Mol Neurodegener 16 (2021): 1-14.

   Google Scholar, Crossref, Indexed at